Genetic and epigenetic fine mapping of causal autoimmune disease variants
Mikhail Dozmorov
November 1, 2014
Genetic and epigenetic fine mapping of causal autoimmune disease variants
Supplemental table 1 has genomic coordinates of disease-associated SNPs.
Analysis of TFBSs
Out of all regulatory datasets, we select only TFBSs.
## [1] 1954 39## [1] 1259 38
Text mining question 1: Are the diseases within a cluster share stronger literature similarity than the diseases between the clusters? To answer, we need literature similarity scores for each pair, then split the pairs into cluster-specific groups and compare score distributions with what can be expected by chance, calculating the p-values for it. Expected answer: Diseases within each cluster are related to each other by literature findings stronger than could be expected by chance. Diseases between the clusters are not related to each other by literature findings, and this also may be statistically significant.
The top 10 pairs of disease-associated SNPs are most similar with each other.
##
## -----------------------------------------------------------------------------------------------
## Disease 1 Disease 2 Corr. coefficient
## ---------------------------------------------- ---------------------------- -------------------
## HDL_cholesterol Triglycerides 0.5484
##
## Kawasaki_disease Systemic_lupus_erythematosus 0.5352
##
## Bone_mineral_density Type_2_diabetes 0.5268
##
## Kawasaki_disease Multiple_sclerosis 0.501
##
## Kawasaki_disease Rheumatoid_arthritis 0.4775
##
## Celiac_disease Kawasaki_disease 0.4754
##
## LDL_cholesterol Triglycerides 0.4743
##
## Kawasaki_disease Ulcerative_colitis 0.4661
##
## Liver_enzyme_levels_gamma_glutamyl_transferase Urate_levels 0.4191
##
## Alzheimers_combined Bone_mineral_density 0.4149
## -----------------------------------------------------------------------------------------------The similarity dendrogram can be divided into separate groups:
## Cluster01 has 8 members
## Kawasaki_disease
## Systemic_lupus_erythematosus
## Celiac_disease
## Ulcerative_colitis
## Psoriasis
## Multiple_sclerosis
## Rheumatoid_arthritis
## Allergy
##
## Cluster02 has 12 members
## Systemic_sclerosis
## Primary_biliary_cirrhosis
## Atopic_dermatitis
## Juvenile_idiopathic_arthritis
## Ankylosing_spondylitis
## Crohns_disease
## Type_1_diabetes
## Primary_sclerosing_cholangitis
## Creatinine_levels
## Behcets_disease
## Progressive_supranuclear_palsy
## Restless_legs_syndrome
##
## Cluster03 has 8 members
## Vitiligo
## Migraine
## Alopecia_areata
## Asthma
## Chronic_kidney_disease
## Alzheimers_combined
## Bone_mineral_density
## Type_2_diabetes
##
## Cluster04 has 10 members
## Urate_levels
## Liver_enzyme_levels_gamma_glutamyl_transferase
## LDL_cholesterol
## HDL_cholesterol
## Triglycerides
## Renal_function_related_traits_BUN
## Platelet_counts
## Red_blood_cell_traits
## C_reactive_protein
## Fasting_glucose_related_traits
## The “Enrichment 1/2” columns show the average p-values of the group-specific SNPs-regulatory associations. A “-” sign indicates that an association is underrepresented. The “p-value” column shows whether the difference in the associations between the groups is statistically significantly different.
## [1] "c1 vs. c2 , number of degs significant at adj.p.val<0.5 and 2-fold diff: 86"
##
## -------------------------------------------------------------------------------------------------------------
## Row.names V2 c1 c2 adj.P.Val
## -------------------------------------------------- ----------------------------- --------- ------ -----------
## wgEncodeSydhTfbsGm18505NfkbTnfaIggrabPk GM18505 NFKB IgG-rab TNFa 3.594e-06 0.9272 0.03671
## ChIP-seq Peaks from
## ENCODE/SYDH
##
## wgEncodeSydhTfbsGm12878Pol2IggmusPk GM12878 Pol2 IgG-mus ChIP-seq 9.774e-06 0.8334 0.003843
## Peaks from ENCODE/SYDH
##
## wgEncodeHaibTfbsGm12878Mta3sc81325V0422111PkRep2 GM12878 MTA3 v042211.1 2.011e-05 0.7491 0.0002624
## ChIP-seq Peaks Rep 2 from
## ENCODE/HAIB
##
## wgEncodeSydhTfbsGm12891Pol2IggmusPk GM12891 Pol2 IgG-mus ChIP-seq 6.286e-05 0.6297 0.03649
## Peaks from ENCODE/SYDH
##
## wgEncodeHaibTfbsGm12878Nficsc81335V0422111PkRep1 GM12878 NFIC v042211.1 6.767e-05 0.5832 0.000109
## ChIP-seq Peaks Rep 1 from
## ENCODE/HAIB
##
## wgEncodeHaibTfbsGm12878Nfatc1sc17834V0422111PkRep2 GM12878 NFATC1 v042211.1 9.584e-05 0.6672 0.0006969
## ChIP-seq Peaks Rep 2 from
## ENCODE/HAIB
##
## wgEncodeHaibTfbsGm12892Pol2V0416102PkRep1 GM12892 Pol2 v041610.2 0.0001446 0.7113 0.004147
## ChIP-seq Peaks Rep 1 from
## ENCODE/HAIB
##
## wgEncodeSydhTfbsGm12878Chd1a301218aIggmusPk GM12878 CHD1 IgG-mus ChIP-seq 0.0001594 0.7835 0.004317
## Peaks from ENCODE/SYDH
##
## wgEncodeHaibTfbsGm12878Pol24h8Pcr1xPkRep1 GM12878 Pol2-4H8 PCR1x 0.0002028 0.965 0.05724
## ChIP-seq Peaks Rep 1 from
## ENCODE/HAIB
##
## wgEncodeHaibTfbsGm12878Pmlsc71910V0422111PkRep2 GM12878 PML v042211.1 0.0001479 0.7001 8.3e-05
## ChIP-seq Peaks Rep 2 from
## ENCODE/HAIB
## -------------------------------------------------------------------------------------------------------------
##
## [1] "c1 vs. c3 , number of degs significant at adj.p.val<0.5 and 2-fold diff: 110"
##
## ---------------------------------------------------------------------------------------------------------------
## Row.names V2 c1 c3 adj.P.Val
## -------------------------------------------------- ----------------------------- --------- -------- -----------
## wgEncodeHaibTfbsGm12878Mta3sc81325V0422111PkRep2 GM12878 MTA3 v042211.1 2.011e-05 -0.03223 9.655e-06
## ChIP-seq Peaks Rep 2 from
## ENCODE/HAIB
##
## wgEncodeSydhTfbsGm12878Pol2IggmusPk GM12878 Pol2 IgG-mus ChIP-seq 9.774e-06 -0.06673 0.0006752
## Peaks from ENCODE/SYDH
##
## wgEncodeSydhTfbsGm18505NfkbTnfaIggrabPk GM18505 NFKB IgG-rab TNFa 3.594e-06 -0.4501 0.03447
## ChIP-seq Peaks from
## ENCODE/SYDH
##
## wgEncodeSydhTfbsGm12891Pol2IggmusPk GM12891 Pol2 IgG-mus ChIP-seq 6.286e-05 -0.1467 0.01099
## Peaks from ENCODE/SYDH
##
## wgEncodeHaibTfbsGm12878Nficsc81335V0422111PkRep1 GM12878 NFIC v042211.1 6.767e-05 -0.1369 8.824e-06
## ChIP-seq Peaks Rep 1 from
## ENCODE/HAIB
##
## wgEncodeHaibTfbsGm12892Pol2V0416102PkRep1 GM12892 Pol2 v041610.2 0.0001446 -0.09939 0.0005075
## ChIP-seq Peaks Rep 1 from
## ENCODE/HAIB
##
## wgEncodeHaibTfbsGm12878Nfatc1sc17834V0422111PkRep2 GM12878 NFATC1 v042211.1 9.584e-05 -0.1597 8.211e-05
## ChIP-seq Peaks Rep 2 from
## ENCODE/HAIB
##
## wgEncodeHaibTfbsGm12878Pmlsc71910V0422111PkRep2 GM12878 PML v042211.1 0.0001479 -0.1222 8.824e-06
## ChIP-seq Peaks Rep 2 from
## ENCODE/HAIB
##
## wgEncodeSydhTfbsGm18505Pol2IggmusPk GM18505 Pol2 IgG-mus ChIP-seq 0.0002114 -0.1043 0.0003008
## Peaks from ENCODE/SYDH
##
## wgEncodeHaibTfbsGm12892Pol24h8V0416102PkRep1 GM12892 Pol2-4H8 v041610.2 0.0003613 -0.06464 0.000142
## ChIP-seq Peaks Rep 1 from
## ENCODE/HAIB
## ---------------------------------------------------------------------------------------------------------------
##
## [1] "c1 vs. c4 , number of degs significant at adj.p.val<0.5 and 2-fold diff: 103"
##
## --------------------------------------------------------------------------------------------------------------
## Row.names V2 c1 c4 adj.P.Val
## -------------------------------------------------- ----------------------------- --------- ------- -----------
## wgEncodeSydhTfbsGm18505NfkbTnfaIggrabPk GM18505 NFKB IgG-rab TNFa 3.594e-06 -0.775 0.03454
## ChIP-seq Peaks from
## ENCODE/SYDH
##
## wgEncodeSydhTfbsGm12878Pol2IggmusPk GM12878 Pol2 IgG-mus ChIP-seq 9.774e-06 -0.3918 0.001616
## Peaks from ENCODE/SYDH
##
## wgEncodeHaibTfbsGm12878Mta3sc81325V0422111PkRep2 GM12878 MTA3 v042211.1 2.011e-05 -0.2356 3.528e-05
## ChIP-seq Peaks Rep 2 from
## ENCODE/HAIB
##
## wgEncodeHaibTfbsGm12878Nficsc81335V0422111PkRep1 GM12878 NFIC v042211.1 6.767e-05 -0.1347 5.071e-06
## ChIP-seq Peaks Rep 1 from
## ENCODE/HAIB
##
## wgEncodeSydhTfbsGm12891Pol2IggmusPk GM12891 Pol2 IgG-mus ChIP-seq 6.286e-05 -0.5071 0.01766
## Peaks from ENCODE/SYDH
##
## wgEncodeHaibTfbsGm12878Pmlsc71910V0422111PkRep2 GM12878 PML v042211.1 0.0001479 -0.3198 9.171e-06
## ChIP-seq Peaks Rep 2 from
## ENCODE/HAIB
##
## wgEncodeHaibTfbsGm12878Nfatc1sc17834V0422111PkRep2 GM12878 NFATC1 v042211.1 9.584e-05 -0.4966 0.0001887
## ChIP-seq Peaks Rep 2 from
## ENCODE/HAIB
##
## wgEncodeHaibTfbsGm12878Mta3sc81325V0422111PkRep1 GM12878 MTA3 v042211.1 0.000339 -0.2 2.35e-05
## ChIP-seq Peaks Rep 1 from
## ENCODE/HAIB
##
## wgEncodeHaibTfbsGm12878Pol24h8Pcr1xPkRep2 GM12878 Pol2-4H8 PCR1x 0.0004474 -0.1903 0.004696
## ChIP-seq Peaks Rep 2 from
## ENCODE/HAIB
##
## wgEncodeHaibTfbsGm12892Pol2V0416102PkRep1 GM12892 Pol2 v041610.2 0.0001446 -0.6038 0.00179
## ChIP-seq Peaks Rep 1 from
## ENCODE/HAIB
## --------------------------------------------------------------------------------------------------------------
##
## [1] "c2 vs. c3 , number of degs significant at adj.p.val<0.5 and 2-fold diff: 0"
##
## -------------------------------------------------------------------------------------------------------------
## Row.names V2 c2 c3 adj.P.Val
## ------------------------------------------------ ----------------------------- --------- -------- -----------
## wgEncodeHaibTfbsMcf7Hdac2sc6296V0422111PkRep2 MCF-7 HDAC2 v042211.1 1.024e-08 -0.9111 0.6711
## ChIP-seq Peaks Rep 2 from
## ENCODE/HAIB
##
## wgEncodeHaibTfbsA549Tead4sc101184V0422111PkRep1 A549 TEAD4 v042211.1 ChIP-seq 2.584e-07 0.7003 0.6885
## Peaks Rep 1 from ENCODE/HAIB
##
## wgEncodeSydhTfbsMcf7Gata3sc269UcdPk MCF-7 GATA3 SC269 UC Davis 5.462e-06 -0.9907 0.6676
## ChIP-seq Peaks from
## ENCODE/SYDH
##
## wgEncodeSydhTfbsH1hescSuz12UcdPk H1-hESC SUZ12 UC Davis 5.736e-06 0.3309 0.7192
## ChIP-seq Peaks from
## ENCODE/SYDH
##
## wgEncodeHaibTfbsMcf7MaxV0422111PkRep2 MCF-7 Max v042211.1 ChIP-seq 0.0001833 0.8041 0.6885
## Peaks Rep 2 from ENCODE/HAIB
##
## wgEncodeHaibTfbsMcf7Tcf12V0422111PkRep1 MCF-7 TCF12 v042211.1 0.002079 0.9427 0.6192
## ChIP-seq Peaks Rep 1 from
## ENCODE/HAIB
##
## wgEncodeSydhTfbsGm12878JundIggrabPk GM12878 JunD IgG-rab ChIP-seq 0.02161 -0.9099 0.7584
## Peaks from ENCODE/SYDH
##
## wgEncodeHaibTfbsGm12878Mta3sc81325V0422111PkRep2 GM12878 MTA3 v042211.1 0.7491 -0.03223 0.4004
## ChIP-seq Peaks Rep 2 from
## ENCODE/HAIB
##
## wgEncodeHaibTfbsHl60Pol24h8V0422111PkRep2 HL-60 Pol2-4H8 v042211.1 0.0397 -0.657 0.4988
## ChIP-seq Peaks Rep 2 from
## ENCODE/HAIB
##
## wgEncodeHaibTfbsGm12892Pol24h8V0416102PkRep1 GM12892 Pol2-4H8 v041610.2 0.4503 -0.06464 0.3761
## ChIP-seq Peaks Rep 1 from
## ENCODE/HAIB
## -------------------------------------------------------------------------------------------------------------
##
## [1] "c2 vs. c4 , number of degs significant at adj.p.val<0.5 and 2-fold diff: 0"
##
## ------------------------------------------------------------------------------------------------------------
## Row.names V2 c2 c4 adj.P.Val
## ------------------------------------------------ ----------------------------- --------- ------- -----------
## wgEncodeHaibTfbsMcf7Hdac2sc6296V0422111PkRep2 MCF-7 HDAC2 v042211.1 1.024e-08 0.7626 0.8601
## ChIP-seq Peaks Rep 2 from
## ENCODE/HAIB
##
## wgEncodeHaibTfbsA549Tead4sc101184V0422111PkRep1 A549 TEAD4 v042211.1 ChIP-seq 2.584e-07 0.8079 0.8601
## Peaks Rep 1 from ENCODE/HAIB
##
## wgEncodeSydhTfbsMcf7Gata3sc269UcdPk MCF-7 GATA3 SC269 UC Davis 5.462e-06 0.9893 0.8463
## ChIP-seq Peaks from
## ENCODE/SYDH
##
## wgEncodeSydhTfbsH1hescSuz12UcdPk H1-hESC SUZ12 UC Davis 5.736e-06 0.8414 0.8601
## ChIP-seq Peaks from
## ENCODE/SYDH
##
## wgEncodeHaibTfbsMcf7MaxV0422111PkRep2 MCF-7 Max v042211.1 ChIP-seq 0.0001833 0.8538 0.8601
## Peaks Rep 2 from ENCODE/HAIB
##
## wgEncodeHaibTfbsMcf7Tcf12V0422111PkRep1 MCF-7 TCF12 v042211.1 0.002079 0.8988 0.8204
## ChIP-seq Peaks Rep 1 from
## ENCODE/HAIB
##
## wgEncodeSydhTfbsGm12878JundIggrabPk GM12878 JunD IgG-rab ChIP-seq 0.02161 -0.9997 0.9213
## Peaks from ENCODE/SYDH
##
## wgEncodeHaibTfbsHl60Pol24h8V0422111PkRep2 HL-60 Pol2-4H8 v042211.1 0.0397 -0.7606 0.7664
## ChIP-seq Peaks Rep 2 from
## ENCODE/HAIB
##
## wgEncodeHaibTfbsGm12878Pol24h8Pcr1xPkRep2 GM12878 Pol2-4H8 PCR1x 0.3719 -0.1903 0.8628
## ChIP-seq Peaks Rep 2 from
## ENCODE/HAIB
##
## wgEncodeHaibTfbsGm12878Nficsc81335V0422111PkRep1 GM12878 NFIC v042211.1 0.5832 -0.1347 0.6952
## ChIP-seq Peaks Rep 1 from
## ENCODE/HAIB
## ------------------------------------------------------------------------------------------------------------
##
## [1] "c3 vs. c4 , number of degs significant at adj.p.val<0.5 and 2-fold diff: 0"
##
## -----------------------------------------------------------------------------------------------------------
## Row.names V2 c3 c4 adj.P.Val
## -------------------------------------------------- ----------------------------- ------ ------- -----------
## wgEncodeSydhTfbsK562Pol2s2StdPk K562 Pol2 S2 Standard 0.143 -0.8604 0.2013
## ChIP-seq Peaks from
## ENCODE/SYDH
##
## wgEncodeSydhTfbsImr90Mazab85725IggrabPk IMR90 MAZ (ab85725) IgG-rab 0.1393 0.6184 0.6938
## ChIP-seq Peaks from
## ENCODE/SYDH
##
## wgEncodeAwgTfbsSydhH1hescSin3anb6001263IggrabUniPk H1-hESC TFBS Uniform Peaks of 0.2549 0.9992 0.221
## SIN3A_(NB600-1263) from
## ENCODE/Stanford/Analysis
##
## wgEncodeUwTfbsBjCtcfStdHotspotsRep1 BJ CTCF TFBS ChIP-seq 0.2954 -0.8671 0.1851
## Hotspots 1 from ENCODE/UW
##
## wgEncodeUwTfbsHmfCtcfStdHotspotsRep1 HMF CTCF TFBS ChIP-seq 0.2174 0.8316 0.1651
## Hotspots 1 from ENCODE/UW
##
## wgEncodeHaibTfbsHct116Rad21V0422111PkRep1 HCT-116 RAD21 v042211.1 0.334 -0.9289 0.1625
## ChIP-seq Peaks Rep 1 from
## ENCODE/HAIB
##
## wgEncodeHaibTfbsEcc1Rad21V0422111PkRep2 ECC-1 RAD21 v042211.1 0.3424 -0.9585 0.1651
## ChIP-seq Peaks Rep 2 from
## ENCODE/HAIB
##
## wgEncodeUwTfbsHbmecCtcfStdHotspotsRep1 HBMEC CTCF TFBS ChIP-seq 0.32 0.9727 0.1651
## Hotspots 1 from ENCODE/UW
##
## wgEncodeHaibTfbsA549Ctcfsc5916Pcr1xEtoh02PkRep1 A549 CTCF 5916 EtOH PCR1x 0.3365 -0.9842 0.1625
## ChIP-seq Peaks Rep 1 from
## ENCODE/HAIB
##
## wgEncodeAwgTfbsSydhH1hescSuz12UcdUniPk H1-hESC TFBS Uniform Peaks of 0.3232 0.9742 0.4938
## SUZ12 from
## ENCODE/USC/Analysis
## -----------------------------------------------------------------------------------------------------------Text mining question 2: Are the terms associated stronger with the diseases in one vs. the other cluster based on the literature strength? Are the terms themselves related based on the literature? Expected answer: Yes, the literature associations should confirm the relationships.
Summary
- There are 4 clusters. The first cluster drives all the differences.
| C1 | C2 | C3 | C4 | |
|---|---|---|---|---|
| C1 | Cell types: Gm12878 Reg: NFkB, Pol2, MTA3, NFIC, NFATC1 | Cell types: Gm12878 Reg: NFkB, Pol2, MTA3, NFIC, NFATC1 | Cell types: Gm12878 Reg: NFkB, Pol2, MTA3, NFIC, NFATC1 | |
| C2 | Nothing significant | Nothing significant | ||
| C3 | Nothing significant | |||
| C4 |
Analysis of histone marks
Out of all regulatory datasets, we select only histone marks
## [1] 721 39## [1] 610 39
Text mining question 1: Are the diseases within a cluster share stronger literature similarity than the diseases between the clusters? To answer, we need literature similarity scores for each pair, then split the pairs into cluster-specific groups and compare score distributions with what can be expected by chance, calculating the p-values for it. Expected answer: Diseases within each cluster are related to each other by literature findings stronger than could be expected by chance. Diseases between the clusters are not related to each other by literature findings, and this also may be statistically significant.
The top 10 pairs of autoimmune-associated SNPs are most similar with each other.
##
## ---------------------------------------------------------------------------------------
## Disease 1 Disease 2 Corr. coefficient
## --------------------------------- --------------------------------- -------------------
## HDL_cholesterol Triglycerides 0.621
##
## Rheumatoid_arthritis Ulcerative_colitis 0.4856
##
## HDL_cholesterol LDL_cholesterol 0.48
##
## HDL_cholesterol Platelet_counts 0.4609
##
## Platelet_counts Triglycerides 0.4504
##
## LDL_cholesterol Triglycerides 0.4151
##
## Creatinine_levels Renal_function_related_traits_BUN 0.3915
##
## Psoriasis Systemic_lupus_erythematosus 0.3911
##
## Renal_function_related_traits_BUN Urate_levels 0.3689
##
## Alopecia_areata C_reactive_protein 0.3686
## ---------------------------------------------------------------------------------------The similarity dendrogram can be divided into separate groups:
## Cluster01 has 6 members
## Celiac_disease
## Multiple_sclerosis
## Kawasaki_disease
## Primary_biliary_cirrhosis
## Systemic_lupus_erythematosus
## Psoriasis
##
## Cluster02 has 14 members
## Type_2_diabetes
## Fasting_glucose_related_traits
## Red_blood_cell_traits
## Crohns_disease
## Migraine
## Systemic_sclerosis
## Ankylosing_spondylitis
## Platelet_counts
## Triglycerides
## HDL_cholesterol
## Vitiligo
## Progressive_supranuclear_palsy
## Liver_enzyme_levels_gamma_glutamyl_transferase
## LDL_cholesterol
##
## Cluster03 has 11 members
## Allergy
## Type_1_diabetes
## Primary_sclerosing_cholangitis
## Juvenile_idiopathic_arthritis
## Behcets_disease
## Ulcerative_colitis
## Rheumatoid_arthritis
## Autoimmune_thyroiditis
## Alopecia_areata
## C_reactive_protein
## Asthma
##
## Cluster04 has 8 members
## Bone_mineral_density
## Chronic_kidney_disease
## Alzheimers_combined
## Restless_legs_syndrome
## Atopic_dermatitis
## Urate_levels
## Renal_function_related_traits_BUN
## Creatinine_levels
## The “Enrichment 1/2” columns show the average p-values of the group-specific SNPs-regulatory associations. A “-” sign indicates that an association is underrepresented. The “p-value” column shows whether the difference in the associations bwtween the groups is statistically significantly different.
## [1] "c1 vs. c2 , number of degs significant at adj.p.val<0.5 and 2-fold diff: 45"
##
## ---------------------------------------------------------------------------------------------------------
## Row.names V2 c1 c2 adj.P.Val
## ------------------------------------------ ----------------------------- --------- ---------- -----------
## wgEncodeBroadHistoneGm12878H3k04me1StdPkV2 GM12878 H3K4me1 Histone Mods 6.263e-15 -0.01015 3.557e-05
## by ChIP-seq Peaks from
## ENCODE/Broad
##
## wgEncodeBroadHistoneGm12878H3k9me3StdPk GM12878 H3K9me3 Histone Mods 2.129e-10 -0.0002502 3.665e-05
## by ChIP-seq Peaks from
## ENCODE/Broad
##
## wgEncodeBroadHistoneGm12878H3k9acStdPk GM12878 H3K9ac Histone Mods 3.849e-12 -0.205 8.601e-07
## by ChIP-seq Peaks from
## ENCODE/Broad
##
## wgEncodeBroadHistoneGm12878H3k27acStdPk GM12878 H3K27ac Histone Mods 2.561e-11 -0.1967 0.0003686
## by ChIP-seq Peaks from
## ENCODE/Broad
##
## wgEncodeBroadHistoneGm12878H2azStdPk GM12878 H2A.Z Histone Mods by 8.379e-11 -0.0708 0.002582
## ChIP-seq Peaks from
## ENCODE/Broad
##
## wgEncodeBroadHistoneCd20H3k04me2Pk CD20+ H3K4me2 Histone Mods by 6.1e-09 -0.06418 3.557e-05
## ChIP-seq Peaks from
## ENCODE/Broad
##
## wgEncodeBroadHistoneGm12878H3k4me2StdPk GM12878 H3K4me2 Histone Mods 8.782e-09 -0.06392 8.601e-07
## by ChIP-seq Peaks from
## ENCODE/Broad
##
## wgEncodeBroadHistoneCd20ro01794H3k27acPk CD20+ RO01794 H3K27ac Histone 1.057e-08 -0.09878 0.005575
## Mods by ChIP-seq Peaks from
## ENCODE/Broad
##
## wgEncodeBroadHistoneCd20H2azPk CD20+ H2A.Z Histone Mods by 5.608e-08 -0.03372 0.000703
## ChIP-seq Peaks from
## ENCODE/Broad
##
## wgEncodeBroadHistoneGm12878H3k04me3StdPkV2 GM12878 H3K4me3 Histone Mods 4.708e-08 -0.167 2.222e-05
## by ChIP-seq Peaks from
## ENCODE/Broad
## ---------------------------------------------------------------------------------------------------------
##
## [1] "c1 vs. c3 , number of degs significant at adj.p.val<0.5 and 2-fold diff: 47"
##
## ------------------------------------------------------------------------------------------------------
## Row.names V2 c1 c3 adj.P.Val
## ------------------------------------------ ----------------------------- --------- ------- -----------
## wgEncodeBroadHistoneGm12878H3k04me1StdPkV2 GM12878 H3K4me1 Histone Mods 6.263e-15 0.2686 0.001041
## by ChIP-seq Peaks from
## ENCODE/Broad
##
## wgEncodeBroadHistoneGm12878H3k9acStdPk GM12878 H3K9ac Histone Mods 3.849e-12 0.2791 2.209e-05
## by ChIP-seq Peaks from
## ENCODE/Broad
##
## wgEncodeBroadHistoneGm12878H3k27acStdPk GM12878 H3K27ac Histone Mods 2.561e-11 0.1264 0.004196
## by ChIP-seq Peaks from
## ENCODE/Broad
##
## wgEncodeBroadHistoneGm12878H2azStdPk GM12878 H2A.Z Histone Mods by 8.379e-11 0.2377 0.01882
## ChIP-seq Peaks from
## ENCODE/Broad
##
## wgEncodeBroadHistoneCd20ro01794H3k27acPk CD20+ RO01794 H3K27ac Histone 1.057e-08 -0.4077 0.01648
## Mods by ChIP-seq Peaks from
## ENCODE/Broad
##
## wgEncodeBroadHistoneGm12878H3k9me3StdPk GM12878 H3K9me3 Histone Mods 2.129e-10 0.03993 0.01648
## by ChIP-seq Peaks from
## ENCODE/Broad
##
## wgEncodeBroadHistoneCd20H3k04me2Pk CD20+ H3K4me2 Histone Mods by 6.1e-09 0.7209 0.000875
## ChIP-seq Peaks from
## ENCODE/Broad
##
## wgEncodeBroadHistoneGm12878H3k79me2StdPk GM12878 H3K79me2 Histone Mods 1.867e-08 -0.4995 7.28e-05
## by ChIP-seq Peaks from
## ENCODE/Broad
##
## wgEncodeBroadHistoneGm12878H3k4me2StdPk GM12878 H3K4me2 Histone Mods 8.782e-09 0.5631 5.197e-05
## by ChIP-seq Peaks from
## ENCODE/Broad
##
## wgEncodeBroadHistoneDnd41H3k04me1Pk Dnd41 H3K4me1 Histone Mods by 9.105e-08 -0.7878 0.0001171
## ChIP-seq Peaks from
## ENCODE/Broad
## ------------------------------------------------------------------------------------------------------
##
## [1] "c1 vs. c4 , number of degs significant at adj.p.val<0.5 and 2-fold diff: 58"
##
## ---------------------------------------------------------------------------------------------------------
## Row.names V2 c1 c4 adj.P.Val
## ------------------------------------------ ----------------------------- --------- ---------- -----------
## wgEncodeBroadHistoneGm12878H3k04me1StdPkV2 GM12878 H3K4me1 Histone Mods 6.263e-15 -0.008689 0.0001299
## by ChIP-seq Peaks from
## ENCODE/Broad
##
## wgEncodeBroadHistoneGm12878H3k9me3StdPk GM12878 H3K9me3 Histone Mods 2.129e-10 -1.413e-05 5.165e-05
## by ChIP-seq Peaks from
## ENCODE/Broad
##
## wgEncodeBroadHistoneGm12878H3k27acStdPk GM12878 H3K27ac Histone Mods 2.561e-11 -0.007023 0.0002497
## by ChIP-seq Peaks from
## ENCODE/Broad
##
## wgEncodeBroadHistoneGm12878H3k9acStdPk GM12878 H3K9ac Histone Mods 3.849e-12 -0.1383 4.143e-06
## by ChIP-seq Peaks from
## ENCODE/Broad
##
## wgEncodeBroadHistoneCd20ro01794H3k27acPk CD20+ RO01794 H3K27ac Histone 1.057e-08 -0.001005 0.001851
## Mods by ChIP-seq Peaks from
## ENCODE/Broad
##
## wgEncodeBroadHistoneGm12878H2azStdPk GM12878 H2A.Z Histone Mods by 8.379e-11 -0.161 0.008068
## ChIP-seq Peaks from
## ENCODE/Broad
##
## wgEncodeBroadHistoneCd20H3k04me2Pk CD20+ H3K4me2 Histone Mods by 6.1e-09 -0.01543 6.552e-05
## ChIP-seq Peaks from
## ENCODE/Broad
##
## wgEncodeBroadHistoneGm12878H3k79me2StdPk GM12878 H3K79me2 Histone Mods 1.867e-08 -0.005656 5.047e-06
## by ChIP-seq Peaks from
## ENCODE/Broad
##
## wgEncodeBroadHistoneGm12878H3k4me2StdPk GM12878 H3K4me2 Histone Mods 8.782e-09 -0.02811 4.143e-06
## by ChIP-seq Peaks from
## ENCODE/Broad
##
## wgEncodeBroadHistoneGm12878H3k04me3StdPkV2 GM12878 H3K4me3 Histone Mods 4.708e-08 -0.01621 2.43e-05
## by ChIP-seq Peaks from
## ENCODE/Broad
## ---------------------------------------------------------------------------------------------------------
##
## [1] "c2 vs. c3 , number of degs significant at adj.p.val<0.5 and 2-fold diff: 32"
##
## --------------------------------------------------------------------------------------------------------
## Row.names V2 c2 c3 adj.P.Val
## ------------------------------------------ ----------------------------- --------- --------- -----------
## wgEncodeBroadHistoneK562H3k36me3StdPk K562 H3K36me3 Histone Mods by 0.001587 -0.009793 0.03505
## ChIP-seq Peaks from
## ENCODE/Broad
##
## wgEncodeBroadHistoneNhekH4k20me1StdPk NHEK H4K20me1 Histone Mods by 0.0009324 -0.0364 0.06562
## ChIP-seq Peaks from
## ENCODE/Broad
##
## wgEncodeBroadHistoneNhdfadH4k20me1Pk NHDF-Ad H4K20me1 Histone Mods 0.001681 -0.02737 0.04472
## by ChIP-seq Peaks from
## ENCODE/Broad
##
## wgEncodeBroadHistoneNhaH3k79me2Pk NH-A H3K79me2 Histone Mods by 0.01045 -0.01294 0.01579
## ChIP-seq Peaks from
## ENCODE/Broad
##
## wgEncodeBroadHistoneA549H3k79me2Dex100nmPk A549 DEX 100 nM H3K79me2 0.008678 -0.02115 0.01579
## Histone Mods by ChIP-seq
## Peaks from ENCODE/Broad
##
## wgEncodeBroadHistoneNhlfH3k79me2Pk NHLF H3K79me2 Histone Mods by 0.005332 -0.05179 0.03198
## ChIP-seq Peaks from
## ENCODE/Broad
##
## wgEncodeBroadHistoneNhdfadH3k79me2Pk NHDF-Ad H3K79me2 Histone Mods 0.01755 -0.02178 0.03732
## by ChIP-seq Peaks from
## ENCODE/Broad
##
## wgEncodeBroadHistoneA549H3k36me3Etoh02Pk A549 EtOH 0.02% H3K36me3 0.01319 -0.03129 0.02689
## Histone Mods by ChIP-seq
## Peaks from ENCODE/Broad
##
## wgEncodeBroadHistoneOsteoH3k79me2Pk Osteoblasts H3K79me2 Histone 0.02111 -0.01993 0.01579
## Mods by ChIP-seq Peaks from
## ENCODE/Broad
##
## wgEncodeBroadHistoneA549H3k79me2Etoh02Pk A549 EtOH 0.02% H3K79me2 0.01245 -0.03612 0.02647
## Histone Mods by ChIP-seq
## Peaks from ENCODE/Broad
## --------------------------------------------------------------------------------------------------------
##
## [1] "c2 vs. c4 , number of degs significant at adj.p.val<0.5 and 2-fold diff: 9"
##
## -------------------------------------------------------------------------------------------------------
## Row.names V2 c2 c4 adj.P.Val
## ---------------------------------------- ----------------------------- --------- ---------- -----------
## wgEncodeBroadHistoneHmecH3k36me3StdPk HMEC H3K36me3 Histone Mods by 0.01773 -0.0002847 0.04273
## ChIP-seq Peaks from
## ENCODE/Broad
##
## wgEncodeBroadHistoneK562H3k36me3StdPk K562 H3K36me3 Histone Mods by 0.001587 -0.00739 0.1287
## ChIP-seq Peaks from
## ENCODE/Broad
##
## wgEncodeBroadHistoneNhekH4k20me1StdPk NHEK H4K20me1 Histone Mods by 0.0009324 -0.05835 0.198
## ChIP-seq Peaks from
## ENCODE/Broad
##
## wgEncodeBroadHistoneK562Nsd2ab75359Pk K562 NSD2 (ab75359) Histone 0.001909 -0.03803 0.1947
## Mods by ChIP-seq Peaks from
## ENCODE/Broad
##
## wgEncodeBroadHistoneK562RestPk K562 REST Histone Mods by 0.007983 -0.01042 0.1487
## ChIP-seq Peaks from
## ENCODE/Broad
##
## wgEncodeBroadHistoneNhdfadH4k20me1Pk NHDF-Ad H4K20me1 Histone Mods 0.001681 -0.1255 0.2067
## by ChIP-seq Peaks from
## ENCODE/Broad
##
## wgEncodeBroadHistoneK562NcorPk K562 NCoR Histone Mods by 0.04478 -0.005174 0.0846
## ChIP-seq Peaks from
## ENCODE/Broad
##
## wgEncodeBroadHistoneGm12878H3k36me3StdPk GM12878 H3K36me3 Histone Mods 0.2219 -0.001063 0.05838
## by ChIP-seq Peaks from
## ENCODE/Broad
##
## wgEncodeBroadHistoneNhekH3k9me1StdPk NHEK H3K9me1 Histone Mods by 0.2002 -0.001186 0.02253
## ChIP-seq Peaks from
## ENCODE/Broad
##
## wgEncodeBroadHistoneHepg2H3k36me3StdPk HepG2 H3K36me3 Histone Mods 0.03916 -0.006255 0.1623
## by ChIP-seq Peaks from
## ENCODE/Broad
## -------------------------------------------------------------------------------------------------------
##
## [1] "c3 vs. c4 , number of degs significant at adj.p.val<0.5 and 2-fold diff: 0"
##
## ------------------------------------------------------------------------------------------------------
## Row.names V2 c3 c4 adj.P.Val
## --------------------------------------- ----------------------------- --------- ---------- -----------
## wgEncodeBroadHistoneHsmmH3k27me3StdPk HSMM H3K27me3 Histone Mods by 3.654e-07 -0.02171 0.4638
## ChIP-seq Peaks from
## ENCODE/Broad
##
## wgEncodeBroadHistoneGm12878H3k9me3StdPk GM12878 H3K9me3 Histone Mods 0.03993 -1.413e-05 0.6051
## by ChIP-seq Peaks from
## ENCODE/Broad
##
## wgEncodeBroadHistoneHmecH3k27me3StdPk HMEC H3K27me3 Histone Mods by 5.588e-06 -0.1737 0.6051
## ChIP-seq Peaks from
## ENCODE/Broad
##
## wgEncodeBroadHistoneNhdfadH3k27me3StdPk NHDF-Ad H3K27me3 Histone Mods 0.0002821 -0.08736 0.6051
## by ChIP-seq Peaks from
## ENCODE/Broad
##
## wgEncodeBroadHistoneHmecEzh239875Pk HMEC EZH2 (39875) Histone 0.006694 -0.008291 0.6051
## Mods by ChIP-seq Peaks from
## ENCODE/Broad
##
## wgEncodeBroadHistoneOsteoH3k27me3Pk Osteoblasts H3K27me3 Histone 0.0006062 -0.1426 0.6051
## Mods by ChIP-seq Peaks from
## ENCODE/Broad
##
## wgEncodeBroadHistoneNhaH3k27me3StdPk NH-A H3K27me3 Histone Mods by 0.0001926 -0.9361 0.6051
## ChIP-seq Peaks from
## ENCODE/Broad
##
## wgEncodeBroadHistoneOsteoP300kat3bPk Osteoblasts P300 KAT3B 0.0004775 -0.5556 0.6051
## Histone Mods by ChIP-seq
## Peaks from ENCODE/Broad
##
## wgEncodeBroadHistoneGm12878Ezh239875Pk GM12878 EZH2 (39875) Histone 0.02094 -0.01915 0.6051
## Mods by ChIP-seq Peaks from
## ENCODE/Broad
##
## wgEncodeBroadHistoneHepg2H3k27me3StdPk HepG2 H3K27me3 Histone Mods 0.0008383 -0.6783 0.6051
## by ChIP-seq Peaks from
## ENCODE/Broad
## ------------------------------------------------------------------------------------------------------Text mining question 2: Are the terms associated stronger with the diseases in one vs. the other cluster based on the literature strength? Are the terms themselves related based on the literature? Expected answer: Yes, the literature associations should confirm the relationships.
Summary
- Again, cluster 1 is strongly distinct. Cluster 2 is less so. Histone marks seem all active.
| C1 | C2 | C3 | C4 | |
|---|---|---|---|---|
| C1 | Cell types: Gm12878, CD20+ Reg: H3K4me1, H3K9me3, H3K9ac, H3K27ac, H2az, H3K4me2 | Cell types: Gm12878, CD20+ Reg: H3K4me1, H3K9me3, H3K9ac, H3K27ac, H2az, H3K4me2 | Cell types: Gm12878, CD20+ Reg: H3K4me1, H3K9me3, H3K9ac, H3K27ac, H2az, H3K4me2 | |
| C2 | Cell types: K562, NHEK, NHDF-Ad, NH-A, HMEC Reg: H3K36me3, H4K20me1, H3K79me2 | Nothing significant | ||
| C3 | Nothing significant | |||
| C4 |
Analysis of all regulatory datasets
Out of all regulatory datasets, we select all. The goal here is to get potentially tighter clustering.
## [1] 4498 39## [1] 2969 39
The top 10 pairs of disease-associated SNPs are most similar with each other.
##
## --------------------------------------------------------------------------------------------
## Disease 1 Disease 2 Corr. coefficient
## ---------------------------------------------- ------------------------- -------------------
## HDL_cholesterol Triglycerides 0.473
##
## LDL_cholesterol Triglycerides 0.4314
##
## Chronic_kidney_disease Urate_levels 0.3742
##
## HDL_cholesterol LDL_cholesterol 0.3475
##
## Bone_mineral_density Type_2_diabetes 0.3225
##
## Multiple_sclerosis Primary_biliary_cirrhosis 0.316
##
## Alzheimers_combined Type_2_diabetes 0.2999
##
## Liver_enzyme_levels_gamma_glutamyl_transferase Urate_levels 0.2976
##
## Fasting_glucose_related_traits Type_2_diabetes 0.2972
##
## Liver_enzyme_levels_gamma_glutamyl_transferase Platelet_counts 0.2944
## --------------------------------------------------------------------------------------------The similarity dendrogram can be divided into separate groups:
## Cluster01 has 14 members
## Platelet_counts
## Liver_enzyme_levels_gamma_glutamyl_transferase
## Red_blood_cell_traits
## LDL_cholesterol
## HDL_cholesterol
## Triglycerides
## Type_2_diabetes
## Fasting_glucose_related_traits
## Bone_mineral_density
## Alzheimers_combined
## Creatinine_levels
## Renal_function_related_traits_BUN
## Urate_levels
## Chronic_kidney_disease
##
## Cluster02 has 25 members
## Multiple_sclerosis
## Kawasaki_disease
## Celiac_disease
## Systemic_lupus_erythematosus
## Psoriasis
## Ulcerative_colitis
## Rheumatoid_arthritis
## Crohns_disease
## Autoimmune_thyroiditis
## Primary_biliary_cirrhosis
## Ankylosing_spondylitis
## Systemic_sclerosis
## Migraine
## Primary_sclerosing_cholangitis
## Juvenile_idiopathic_arthritis
## Atopic_dermatitis
## Alopecia_areata
## C_reactive_protein
## Allergy
## Type_1_diabetes
## Vitiligo
## Behcets_disease
## Progressive_supranuclear_palsy
## Restless_legs_syndrome
## Asthma
## The “Enrichment 1/2” columns show the average p-values of the group-specific SNPs-regulatory associations. A “-” sign indicates that an association is underrepresented. The “p-value” column shows whether the difference in the associations bwtween the groups is statistically significantly different.
## [1] "c1 vs. c2 , number of degs significant at adj.p.val<0.5 and 2-fold diff: 0"
##
## --------------------------------------------------------------------------------------------------------------
## Row.names V2 c1 c2 adj.P.Val
## ------------------------------------------------- ----------------------------- --------- -------- -----------
## wgEncodeHaibTfbsMcf7Hdac2sc6296V0422111PkRep2 MCF-7 HDAC2 v042211.1 1.561e-07 0.8353 0.4918
## ChIP-seq Peaks Rep 2 from
## ENCODE/HAIB
##
## wgEncodeHaibTfbsA549Tead4sc101184V0422111PkRep1 A549 TEAD4 v042211.1 ChIP-seq 2.373e-06 0.7976 0.4968
## Peaks Rep 1 from ENCODE/HAIB
##
## wgEncodeSydhTfbsH1hescSuz12UcdPk H1-hESC SUZ12 UC Davis 1.619e-05 0.6341 0.4822
## ChIP-seq Peaks from
## ENCODE/SYDH
##
## wgEncodeSydhTfbsMcf7Gata3sc269UcdPk MCF-7 GATA3 SC269 UC Davis 4.078e-05 0.7946 0.5005
## ChIP-seq Peaks from
## ENCODE/SYDH
##
## wgEncodeGisChiaPetMcf7EraaInteractionsRep2 MCF-7 ERalpha a ChIA-PET 0.0008577 -0.1465 0.1052
## Interactions Rep 2 from
## ENCODE/GIS-Ruan
##
## wgEncodeBroadHistoneNhekH4k20me1StdPk NHEK H4K20me1 Histone Mods by 0.003353 -0.0967 0.1683
## ChIP-seq Peaks from
## ENCODE/Broad
##
## wgEncodeCshlLongRnaSeqK562ChromatinTotalJunctions K562 chromatin total RNA-seq 0.02711 -0.01382 0.3846
## Junctions Pooled from
## ENCODE/CSHL
##
## wgEncodeGisRnaPetK562NucleusPapClustersRep1 K562 nucleus polyA+ 0.005089 -0.07474 0.1233
## clone-based RNA PET Clusters
## Rep 1 from ENCODE/GIS
##
## wgEncodeGisRnaPetK562ChromatinTotalClustersRep1 K562 chromatin total 0.01422 -0.03698 0.1849
## clone-based RNA PET Clusters
## Rep 1 from ENCODE/GIS
##
## wgEncodeGisRnaPetHepg2CytosolPapClustersRep1 HepG2 cytosol polyA+ 0.006008 -0.1193 0.1068
## clone-based RNA PET Clusters
## Rep 1 from ENCODE/GIS
## --------------------------------------------------------------------------------------------------------------Summary
The picture is not as good as when we are taking subsets of regulatory datasets.